Research teams from the United Kingdom and Germany have published their results in the Advance Online Publication on the website of Nature Cell Biology.

The teams belong to the Centre for Molecular Biology at the University of Heidelberg and to the Department of Biochemistry at the University of Leicester. The work of the teams had the support of the DFG (German Research Foundation), Wellcome Trust, Cancer Research UK and the Association for International Cancer Research.

The study was led by Professor Elmar Schiebel from the University of Heidelberg who said that the study described new and important insights into a fundamental process involved in the division of the cell. The results suggest new approaches to a targeted treatment of cancer.

The leader of the team belonging to the University of Leicester, Professor Andrew Fry, added that this exciting new development offered potential for identifying new ways of inhibiting unregulated division of the cell which was characteristic to cancer. The team already works with other colleagues in London and Newcastle to develop the research.

Investigators of the processes involved in the division of the cell identified a new potential breakthrough. As Professor Fry explained, when cells divide they have to accurately separate the genetic material of a scaffolding structure, the mitotic spindle. Cells divide in two and therefore the mitotic spindle scaffold presents two poles to which genetic material, which is carried on chromosomes, must separate.

The poles of this spindle are generated by centrosomes, which are normally held in the close proximity in cells. At the start of the division, they move to the cell’s opposite ends. When the centrosome separation fails, the division of the cell is blocked and this process can lead to the death of the cell.

As the researchers said, their studies identified new proteins that are in control of centrosome separation and assessed the relative contribution of these together with regulators described previously. The research suggests new approaches to targeted treatment of all diseases characterised by irregular cell division, such as cancer is. Inhibitors of centrosome separation may have the potential to prevent anarchical proliferation of cells.

Combining drugs against several regulators may also reduce cytotoxic side-effects thanks to the reduced concentration of each inhibitor used in patients.

The teams of researchers are now developing inhibitors against centrosome separation regulators in order to undertake proofs of principle experiments. They collaborate with the Institute of Cancer Research in London and also the Northern institute for Cancer Research at the Newcastle University.

Results obtained in a phase I clinical study of the new drug were presented in Berlin, on November 19th, at the 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. ACE-041 aims at the receptor known as ALK-1 (activin receptor-like kinase-1), which is responsible for regulating the formation of new networks containing blood vessels that are needed for the growth of tumours. This process is known as angiogenesis. Existing anti-angiogenic drugs, including sunitinib, bevacizumab and sorafenib are targeting other angiogenesis receptors like VEGF, while ACE-041 is among the first drugs to target the ALK-1.

Professor Sunil Sharma, who is the Jon and Karen Huntsman Presidential Professor of Cancer Research at the Huntsman Cancer Institute of the Utah University in Salt Lake City, USA, said that the connection between angiogenesis and ALK-1 was made by discovering that mutations in the ALK-1 gene had caused a condition named HHT2 (hereditary haemorrhagic telangiectasia 2, characterised by diminished formation of capillary beds, which causes red markings at the level of the skin.

A technology company in Cambridge, Massachusetts, USA, Acceleron Pharma, has designed ACE-041 aiming to inhibit ALK-1 signalling and has asked Professor Sharma to be one of the investigators who would conduct the first-in-man phase I clinical test of the drug in order to see if it really would halt tumour angiogenesis.

Professor Sharma said that since ALK-1 was transiently expressed on proliferating cells lining the inner surface of the blood vessels (endothelial cells), while VEGF receptors were constitutively expressed on endothelial cells and other types too, it would be a more selective target when trying to inhibit angiogenesis. ALK-1 expression on the vasculature of the tumour has been noticed on biopsy samples of a wide range of tumours.

The phase I of the study comprised patients with a diversified range of advanced solid tumours that already spread to other parts of the body or simply were inoperable like multiple myeloma, neck and head cancers, NSCLC (non-small cell lung cancer) and carcinoid tumours (carcinoma type neuroendocrine tumours usually originating in the appendix or small intestine). Many of the patients had been unsuccessfully treated with a series of other treatments, which included anti-VEGF drugs, before this trial. ACE-041 has been administrated via subcutaneous injections.

Professor Sharma said that, early in September, 25 patients have been included in the study and ACE-041 dose level has been escalated from 0.1 mg/kg to 4.8 mg/kg. In the case of a patient with neck and head cancer, the response was partial, while three patients have shown positive responses as determined by FDG-PET scans. ACE-041 has been well tolerated by the patients, with some adverse events like peripheral oedema, anaemia, headache, nausea and fatigue.

Seeing many signs of efficacy during the trial has been quite encouraging for the medical team, particularly because of the structure of the study population. They were patients with end-stage cancer, already treated with and refractory to multiple standard therapies. It has equally been encouraging to note signals of activity of ACE-041 in a wide series of tumour types, thus confirming the hypothesis that ACE-041 may really act against tumours with agiogenic activity, no matter what histology they had. Another important aspect to be noted was the demonstration of the significant activity with ACE-041 monotherapy during the study, which leads to expectations of more efficacy in future studies including ACE-041 combined with other therapies.

Professor Sharma and his team planned further investigations related to the safety and tolerability of ACE-041 in an additional group of cancer patients and look forward to start a phase II study in 2011.

According to Professor Sharma, the anti-VEGF angiogene inhibitors, which include sunitinib, bevacizumab and sorafenib, have represented an important contribution to the armamentarium of therapies against cancer. However, the efficacy is in a way limited because tumours could eventually develop an ability to simulate angiogenesis using non-VEGF angiogenic factors. Serious side-effects appear from effects on blood vessels found in normal tissues. ACE-041 inhibits angiogenesis in a totally different way and therefore it might have synergistic efficacy with VEGF-based inhibitors. It may be effective for patients who have manifested resistance to VEGF inhibitors.

In the United States, lung cancer is the second most found type of cancer. It accounts for more dead people than prostate, breast and colon cancer together, as data from the Centers for Disease Control and Prevention show. Many patients follow more than a single type of treatment for lung cancer, which can last for some weeks to months.

Raimar Löbenberg, lead researcher, and his team mates Wilson Roa and Warren Finlay from the University of Alberta, using a usual chemotherapy drug which was encapsulated into nanoparticles, developed a dry powder to be inhaled.
A number of mice were treated with this powder and others received the same drug through two distinct delivery methods, consisting of a solution and intravenous injection of drug bound nanoparticles.

Results have shown the inhalable dry powder as being more effective than the solution or the intravenous injection. According to the study, more than eighty percent of the mice lived more than ninety days. More than seventy percent of the mice lived for 140 days. At the same time, none of the animals treated with the solution or the intravenous injection survived more than fifty days.

Löbenberg said that current treatments for lung cancer could cost the patient a lot. The research showed that the new treatment method might increase the survival rate and at the same time could be less toxic for the patients’ bodies.

The new inhalable dry powder also proved its efficiency versus the intravenous injection in reducing both the amount and the size of tumors. The animals not treated or treated with the solution or intravenous injection presented large tumor masses, while mice treated with the inhalable dry powder showed significantly fewer and also smaller tumors.

The study furnishes a priceless source for news as well as for feature editors and is divided into key sections which range from the usual question “Why should somebody exercise?” to saying that a person is too busy and does not have the time to do it. Numerous health conditions are covered by the review, such as cancer, stroke, dementia, heart disease, depression, type 2 diabetes, high blood pressure and obesity.

People who practice physical exercises daily have a reduced risk of developing about two dozen physical as well as mental conditions, among which some forms of cancer and dementia, and also can have the deterioration of their body, due to aging, slowed down.

The December issue of IJCP, the International Journal of Clinical Practice, published an extensive research report which shows that apart of abstaining from smoking, remaining physically active is the best lifestyle alternative that any individual can choose in order to improve their health.

Leslie Alford, physiotherapist and lecturer at the University of East Anglia, re-examined forty papers which covered the latest results of international research published from 2006 to 2010.

According to Mr. Alford, the studies reviewed show that a complex mix of factors determines how long a person lives and how healthy will he/she be. Such factors are the person’s lifestyle, the place where he/she lives and sometimes luck. However, individuals do have elements of control over some factors that include smoking, diet, obesity and physical activity.

Physical activity is a key factor for both men and women and is also relevant to all age groups.

The following benefits have been identified by the report:
Diminished risk of coronary heart condition as well as haemorrhagic and ischaemic stroke can be obtained through moderate to intense physical activity.
Physical activity is, according to recent evidence, able to reduce the risk of diseases like certain types of cancer, type 2 diabetes, osteoporosis, depression, high blood pressure and obesity.
Evidence of benefits brought by physical activity in the prevention as well as management of cancer is increasing and an association has been established between more intense physical activity and lower rates of cancer death.
Research has revealed that cycling or even walking for half an hour daily at least determines a decrease in cancer and increasing physical activity to an hour per day produces a 16 percent diminution in cancer incidence.
When coming to specific forms of cancer, evidence is mixed. A strong relationship has been shown between more intense physical activity and a reduced rate of colon cancer regardless of the sex. Similarly, men being more active at work and not sitting too much at a desk presented lower rates of incidence of prostate cancer.
Other studies related to cancer show that, after diagnosis, physical activity has a beneficial influence in recovery and can improve outcomes.
According to studies, men who keep being physically active also experience less erection problems.
The risk of dementia for elderly persons is shown as diminished when physical activity is present.

The review identified some recommendations:
About 150 minutes of physical activity with a moderate intensity would be necessary weekly for healthy adults who are aged between 18 and 65. For example, brisk walking 30 minutes, five days weekly would be of great help. People who want a more intense exercise like jogging would need 20 minutes a day for three days weekly.
In the case of older people, exercise is supposed to bring more flexibility and to maintain their balance.
Physically active people should keep on exercising even when they turn middle aged or elderly. Those who are not very active should increase the level of their physical activity.
Other recommendations refer to not smoking and also following healthy diets.

Mr. Alford said that ideally, in order to enjoy maximum health, people should not smoke, eat healthy, exercise and have a body mass index not above 25. The more such healthy traits are present at an individual, the less likely he/she is to develop chronic disorders. If people cannot give up smoking or maintain a proper weight, they still get health benefits if they increase the level of regular exercises.

Researchers point out that physical inactivity is likely to generate a range of pathophysiological changes to human bodies. It seems that our bodies, as a result of the evolution, are used to a certain amount of physical activity, but many people do not reach such levels anymore due to their sedentary lifestyles.

As a conclusion of the research, both men and women of any age have to be encouraged to become more physically active to gain long-term health.

Mitch McVey, Assistant Professor of Biology, and his team of researchers report that PolQ (DNA polymerase theta) could promote a wrong repair process, supposed to be the cause of mutations, cell death and even cancer. The research has been published in the open-access PLoS Genetics journal, the 1st of July edition.

Scientists have been aware for many years that the DNA polymerase theta is in a way related to cancer development, but the exact cellular role it has is difficult to reveal, according to McVey. It is known that its action during incorrect DNA repair might have implications for those biologists who analyze genomic modifications associated with cancer.

The DNA molecule is double stranded and shaped in the form of a spiral staircase. The two strands are connected together by nucleotides like adenine, cytosine, guanine and thymine, which naturally complement each other. Under normal circumstances, a guanine nucleotide corresponds to a cytosine, while an adenine corresponds to a thymine.

During a cell’s life, it may occur that the staircase is cut off into two molecules. The breaks are to be repaired if cells are supposed to replicate accurately and transmit their genetic material. An important part of these breaks is fixed fast and accurately during a process named HR (homologous recombination). This process uses for repair a template formed of an intact DNA copy. There is, however, a second process, named end-joining repair, which is susceptible of errors. It stitches back together the broken stranded ends without considering the original sequence. Thus, the ends of the strands may be modified by addition or removal of little DNA segments that could alter the genomic architecture.

Mitch McVey and Amy Marie Yu, a doctoral student, have demonstrated an alternative structure of end-joining after studying how repair goes on when DNA ligase 4 is absent. DNA ligase 4 is an important protein which connects together two broken ends of DNA.

Two things have been observed during the analysis of breaks inaccurately repaired in Drosophila melanogaster, the fruit fly. One thing was that extra nucleotides were added to the DNA strands were the breaks were present. Secondly, the insertions were tightly related to the DNA original sequences that were adjacent to the breaks.

The authors have shown that polymerase theta has a dominant role to play in the alternative repair process. It reads first the genetic material present in the DNA neighboring the break and constructs a copy of its structure. The copy of the DNA is then used as a molecular sliver which holds together the ends of the broken strand until they are able to join permanently. The PolQ protein is also believed to be able to unwind the sequences of DNA in the neighborghood of a break and this way facilitates alternative end-joining.

Levels of the protein have been demonstrated to be higher in many types of tumors present at the human, as other groups of researchers have previously shown. McVey’s team is currently working to find out if an alternative type of end-joining depending on the PolQ protein is eventually involved in human cancer. If this is found to be true, then there would be a new target for developing new cancer drugs and this would be the PolQ protein. The first goal of the team is to establish which parts of the protein are playing an active role in alternative end-joining. This could give the team a road map for studying how the activity of the protein has to be altered in order to achieve the expected results.

The National Science Foundation together with the Ellison Medical Foundation has funded the work of McVey’s team.